Artesunate powders, pharmaceutical compositions and methods of manufacture

Abstract

Disclosed herein are powders including a therapeutically effective amount of 4-oxo-4-[[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0 4,13 .0 8,13 ]1exadecane-10-yl]oxy]butanoic acid (artesunate) or a pharmaceutically acceptable salt thereof that can be easily manufactured, sterilized and packaged. Processes for producing these powders and pharmaceutical compositions containing these powders are also disclosed.

What is claimed is: 
     
       1. A method of treating a malaria in a subject in need thereof, the method comprising
 obtaining a micronized powder comprising a therapeutically effective amount of 4-oxo-4-[[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.0 4,13 .0 8,13 ]hexadecan-10-yl]oxy]butanoic acid (artesunate) or a pharmaceutically acceptable salt thereof, 
 wherein the micronized powder contains:
 (i) a crystalline form of artesunate or the pharmaceutically acceptable salt thereof in a concentration above 0 wt % to about 1 wt % of the total weight of the powder, and 
 (ii) has an average static charge from about −0.05 kV to 0.05 kV according to a static charge test that includes: (i) subjecting the powder to a relative humidity of about 30% to 40% for at least five days, (ii) placing the powder onto a piece of weighing paper, (iii) measuring the static charge of the powder with a static meter at least three times, wherein the measuring of the static charge of the powder with a static meter occurs at least 25 millimeters from the surface of the powder, and (iv) calculating the average static charge from the measured static charges; and, 
 
 wherein the micronized powder has been prepared according to a process comprising:
 (i) packaging the micronized powder, 
 (ii) sterilizing the micronized powder, and 
 (iii) filling the sterilized micronized powder into a container at a relative humidity of 30% to 40% at a temperature from 15° C. to 30° C.; 
 
 mixing the micronized powder with a buffer solution to create a pharmaceutical composition; and 
 administering the pharmaceutical composition to the subject in need of malaria treatment. 
 
     
     
       2. The method of  claim 1 , wherein the buffer solution is a bicarbonate buffer solution comprising sodium phosphate monobasic monohydrate, sodium phosphate dibasic dihydrate, sodium hydroxide, phosphoric acid, and water. 
     
     
       3. The method of  claim 1 , wherein the buffer solution has a pH in the range of about 7.9 to 8.1. 
     
     
       4. The method of  claim 1 , wherein the buffer solution contains phosphate ions in the range of about 0.25 to 0.35 M. 
     
     
       5. The method of  claim 1 , wherein the buffer solution is sterilized before the mixing. 
     
     
       6. The method of  claim 1 , wherein the pharmaceutical composition is administered via intravenous injection. 
     
     
       7. The method of  claim 6 , wherein the pharmaceutical composition is administered as a slow IV infusion. 
     
     
       8. The method of  claim 7 , wherein the pharmaceutical composition is administered as the slow IV infusion for a time up to 5 minutes. 
     
     
       9. The method of  claim 1 , wherein the pharmaceutical composition is administered to the subject in an amount ranging from about 1 mg/kg to 8 mg/kg. 
     
     
       10. The method of  claim 1 , wherein the pharmaceutical composition is intravenously administered to the subject in an amount ranging from about 2-3 mg/kg of body weight for at least three days. 
     
     
       11. The method of  claim 1 , wherein the pharmaceutical composition is intravenously administered to the subject in an amount of about 2.4 mg/kg. 
     
     
       12. The method of  claim 11 , wherein the pharmaceutical composition is intravenously administered to the subject for at least three days. 
     
     
       13. The method of  claim 1 , wherein the pharmaceutical composition is parenterally administered to the subject in an amount of about 10 mg/mL. 
     
     
       14. The method of  claim 1 , wherein the micronized powder absorbs moisture in an amount from about 0.01 wt % to 0.03 wt %, based on the total weight of the micronized powder. 
     
     
       15. The method of  claim 1 , wherein the micronized powder has an angle of repose of less than 40° when passing through a funnel with an opening of 8 mm to 12 mm. 
     
     
       16. The method of  claim 1 , wherein the micronized powder has a particle size possessing a D90 of less than 20 μm, a D100 of less than 100 μm, or a D50 of less than 5 μm. 
     
     
       17. The method of  claim 1 , wherein the artesunate or pharmaceutically acceptable salt thereof is free of  Corynebacterium auris  growth. 
     
     
       18. The method of  claim 1 , wherein the micronized powder comprises no more than about 0.5% water, no more than about 0.5% dihydroartemisinin, no more than about 0.2% didehydrodeoxyartemisinin, and no more than about 0.2% of other impurities. 
     
     
       19. The method of  claim 1 , wherein the micronized powder has a Hausner ratio of at least 1.6 when subjected to a relative humidity from about 30% to 40%. 
     
     
       20. The method of  claim 1 , wherein the crystalline form of artesunate or the pharmaceutically acceptable salt thereof is 10-α artesunate. 
     
     
       21. The method of  claim 1 , wherein the micronized powder has a bulk density below 0.2 g/mL. 
     
     
       22. The method of  claim 1 , wherein the micronized powder has a tap density above 0.3 g/mL. 
     
     
       23. The method of  claim 1 , wherein the packaging of the micronized powder comprises packing the micronized powder in at least three polyethylene containers. 
     
     
       24. The method of  claim 1 , wherein the sterilizing of the micronized powder comprises sterilizing the micronized powder with ethylene oxide.